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Proceedings of the National Academy of Sciences of the United States of America

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Abstract

RORγt⁺ T H 17 cells are a proinflammatory CD4⁺ T-cell population associated with autoimmune tissue injury. In mice, priming of T H 17 requires TGF-β, which alone directs the priming of FOXP3⁺ regulatory T cells (Treg), in association with inflammatory cytokines. Priming of human T H 17 cells from conventional naive CD4⁺ T cells under similar conditions, however, has proved difficult to achieve. Here, we report that differentiation of human T H 17 cells preferentially occurs from FOXP3⁺ naive Treg (NTreg) in the presence of IL-2 and IL-1β and is increased by IL-23 and TGF-β. IL-1β–mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of RORγt along with down-regulation of FOXP3. IL-17–secreting cells in NTreg cultures cosecreted TNF-α and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-γ and other T H 17-associated cytokines. Polarized NTreg contained significant subpopulations of CCR6-expressing cells that were highly enriched in IL-17–secreting cells. Finally, analysis of CCR6 expression with respect to that of IL-1RI identified distinct IL-17–secreting subpopulations that had maintained or lost their suppressive functions. Together our results support the concept that priming of human T H 17 from naive CD4⁺ T cells preferentially takes place from FOXP3⁺ Treg precursors in the presence of lineage-specific polarizing factors.